Mechanisms underlying cutaneous photosensitivity in heritable erythropoietic protoporphyria (EPP) will be investigated. EPP currently exists in many unrecognized forms. Its mechanisms of expression are chiefly undetermined. Whether bone marrow or liver is the major site of excess protoporphyrin (PP) synthesis, and what determines onset and severity of liver damage in EPP are questioned. Whether or not heme synthetase is defective, and what may be the role of blood zinc values (compared to non-photosensitive protoporphyrinemics and normals where ZnPP is the major species) are unresolved questions. Parallel studies in a mouse model for human EPP with hepatic protoporphyria, an available population of 30 EPP patients, and other suitable controls are proposed to gain insight into these questions. Goals of our proposal are to identify mechanisms related to rational treatment for EPP and other sunlight-induced dermatoses, and to better understand how excited porphyrin damages skin. Newly developed rapid quantitative PP assays will be applied in 50-100 known porphyrics, mouse protoporphyria, and normals under experimental conditions with numbers and frequency of observations heretofore impractical. Clinical screening programs to find EPP cases will be expanded. Investgations relating amounts and types of porphyrin in blood (in several porphyrias) to acuteness of photosensitivity are proposed. Determinants of liver disease in EPP will be examined by correlating histopathologic changes in biopsies of EPP and control liver, with RBC and plasma PP, serum hemopexin and albumin, liver chemistries, and photosensitivity. Skin and liver from EPP (and controls) will be assessed for localization of protein porphyrin carriers by a new immunohistochemical method. Patterns of complement deposition will be assessed by immunologic techniques. Erythropoietic determinants of disease in EPP will be further assessed by 1) assay of heme synthetase in bone marrow 2) comparison of zinc levels in EPP blood vs. non-photosensitive protoporphyrinemics and normals by atomic absorption spectroscopy and 3) evaluation of PP kinetics in EPP blood compared to the mouse protoporphyria model.